Cellular Protein Nrf1 Protects Against Fatty Liver

MedicalResearch.com Interview with:

Gokhan S. Hotamisligil MD PhD

Dr. Hotamisligil

Gokhan S. Hotamisligil MD PhD
J.S. Simmons Professor of Genetics and Metabolism
Chair, Department of Genetics and Complex Diseases
Department of Genetics and Complex Diseases
Department of Nutrition
Harvard Stem Cell Institute

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Cholesterol is often considered a ‘bad’ nutrient, as it has been strongly linked to a cluster of metabolic diseases. In reality however, cholesterol is absolutely vital for the health of all animal cells, serves as an essential building block for all membranes and precursor for essential molecules.  It usually only becomes toxic when cells are exposed to high levels or free forms of cholesterol or when it is stored in excess.

The reasons why cholesterol over-accumulates or causes excessive damage in cells of some people is not entirely clear, as cells are normally should be able to remove such excesses, and there remains key mechanistic gaps in our understanding of how cells control the molecular process of sensing excess cholesterol, engage ways of removal and launch countermeasures to defend their integrity. Filling this gap may reveal a new path toward alleviating the burden of cholesterol-related diseases.

To this end, we identified a new signal pathway mediated by a protein called Nrf1, which enables cells to know when to remove cholesterol, thereby preventing excess cholesterol storage. We show that Nrf1 directly senses cholesterol in a strategic subcellular compartment called the endoplasmic reticulum and coordinates an adaptive and defensive responses that protects the cells and promotes the removal of cellular cholesterol. Continue reading

Praluent Plus Statins Reduce LDL In High Risk Cardiovascular Patients

MedicalResearch.com Interview with:

VP Head of Cardiovascular Development and Head Global Cardiovascular Medical Affairs Sanofi

Dr. Edelberg

Dr. Jay Edelberg MD, PhD
VP Head of Cardiovascular Development and
Head Global Cardiovascular Medical Affairs
Sanofi 

MedicalResearch.com: What should readers take away from the data that Sanofi and Regeneron is presenting at ESC Congress 2017?   

Response: This year at European Society of Cardiology (ESC,) we are pleased to present analyses that further demonstrate additional efficacy and tolerability of Praluent (alirocumab).

While statins remain the first-line treatment, Praluent has shown a consistent benefit as an additional therapy to high-intensity statins in patients with clinical atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH), allowing many patients to achieve low-density lipoprotein (LDL) cholesterol levels previously considered unattainable in this patient population.

Our data further emphasize the need for additional cholesterol-lowering options in these high cardiovascular (CV) risk patient populations, including individuals living with diabetes 

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Positive Emotions Predict Health Lipid Profiles In Western, But Not Eastern Cultures

MedicalResearch.com Interview with:

Jiah Yoo Ph.D. Student in Social Psychology University of Wisconsin-Madison Madison, WI 53706 

Jiah Yoo

Jiah Yoo
Ph.D. Student in Social Psychology
University of Wisconsin-Madison
Madison, WI 53706 

MedicalResearch.com: What is the background for this study?

Response: A growing number of studies have shown that positive emotions predict better physical health. However, a caveat of these findings is that most studies have been conducted with Western samples. As cultural psychologists, we have learned that European American cultural contexts are particular in that positive emotions are highly valued and emphasized. For example, in East Asian cultures, it is a commonly shared view that positive emotions have some dark sides such as that they are fleeting, may attract unnecessary attention from others, and can be a distraction from focusing on important tasks. Given the cultural differences in emotions, we thought it would be important to test whether the established link between positive emotion and enhanced physical health are relevant to other cultural contexts, such as those in East Asia.

We focused on blood lipids profiles, one of the major risk factors for heart diseases, as objective measures of health. Because of the global prevalence of coronary artery diseases, blood lipids are considered important indices of biological health in many Western and East Asian countries. In addition, blood lipids are largely influenced by lifestyles and behavioral factors so we further tested the role of various health behaviors (i.e., dietary habits, body mass index, smoking, alcohol consumption) in the lipids-emotion link in different cultures.

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Hyperlipidemia Linked To Lower Breast Cancer Mortality, Perhaps Due To Statin Therapy

MedicalResearch.com Interview with:

Dr Rahul Potluri Senior author and founder of the ACALM Study Unit Aston Medical School Aston University Birmingham, UK

Dr. Potluri

Dr Rahul Potluri
Senior author and founder of the ACALM Study Unit
Aston Medical School
Aston University
Birmingham, UK

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The links between hyperlipidaemia and cancer has been exciting scientists in recent years.  We have previously shown an association with breast cancer and hyperlipidaemia using a cross-sectional dataset in 2014.

In 2016 we showed that in patients with the four main cancers in the UK (namely Breast, Lung, Colon and Prostate) that the presence of hyperlipidaemia improved the long term mortality and prognosis of these patients.  In this study utilising a big data, longitudinal study methodology, we looked at 16043 healthy women above the age of 40 with hyperlipidaemia and compared these to an age and gender matched control sample of 16043 healthy women without high cholesterol. We then followed up these patients and found that subsequent breast cancer rates in the women with hyperlipidaemia were 45% lower. Subsequent mortality in those patients who developed breast cancer was also 40% lower in the hyperlipidaemia group compared to the non-hyperlipidaemia controlled sample.

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Even After Rebates, Use of PCSK9 Inhibitor Would Still Cost Over $5 Million To Prevent One Stroke

MedicalResearch.com Interview with:

Inmaculada Hernandez, PharmD, PhD Assistant Professor of Pharmacy and Therapeutics University of Pittsburgh School of Pharmacy Pittsburgh, PA 1526

Dr. Hernandez

Inmaculada Hernandez, PharmD, PhD
Assistant Professor of Pharmacy and Therapeutics
University of Pittsburgh School of Pharmacy
Pittsburgh, PA 1526

MedicalResearch.com: What is the background for this study?

Response: A few months ago, the results of the FOURIER trial were published. This trial was the first one to evaluate the efficacy of PCSK9 inhibitors in the prevention of cardiovascular events, since the approval of these agents was based on trials that evaluated their efficacy in reducing levels of LDL-C. The results of the FOURIER trial did not meet the expectations generated by prior studies that had simulated how much the risk of cardiovascular events should decrease based on the observed reduction in LDL-C levels. A few hours after the publication of the results of the FOURIER trial, Amgen (evolocumab´s manufacturer) announced that it would be willing to engage in contracts where the cost of evolocumab would be refunded for those patients who suffer a heart attack or a stroke while using the drug.

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PCSK9 Inhibitor Praluent Added to Statins Improved Lipid Profile in Diabetes

MedicalResearch.com Interview with:

Dr-Robert-R-Henry.jpg

Dr. Henry

Robert R. Henry, M.D.
Professor of Medicine
Member of the ODYSSEY DM Steering Committee and
Director of the Center for Metabolic Research
VA San Diego Healthcare System

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The ODYSSEY DM-DYSLIPIDEMIA trial was a randomized, open-label, parallel-group study designed to evaluate the superiority of Praluent versus usual care in 413 patients with type 2 diabetes with mixed dyslipidemia at high cardiovascular (CV) risk, not adequately controlled with maximally tolerated dose (MTD) statins. The primary endpoint was percent change in non-high-density lipoprotein cholesterol (non-HDL-C) from baseline to week 24.

In ODYSSEY DM-DYSLIPIDEMIA, Praluent 75 mg was added to MTD statins, with dose adjusted at week 12 to 150 mg every two weeks if their non-HDL-C was greater than or equal to 100 mg/dL at week 8. Approximately 64 percent of patients reached their lipid goals with the Praluent 75 mg dose.

Results from the ODYSSEY DM-DYSLIPIDEMIA study found that Praluent added to MTD statins showed significant reduction in non-HDL-C and other lipid parameters compared to those on usual care.

Praluent was superior to usual care in lowering non-HDL-C (37.3 percent and 4.7 percent, for the usual care arm). The mean difference between the two treatment arms was -32.5 percent (p<0.0001).

Praluent in combination with MTD statins reduced LDL-C by 43 percent from baseline compared to a 0.3 percent increase for usual care (p<0.0001). Treatment with Praluent also improved the overall lipid profile.

There is a large unmet need for improving cholesterol lowering in patients with diabetes. Despite current standard of care, nearly 70 percent of people age 65 or older with diabetes die from some form of heart disease; and 16 percent die of stroke. Furthermore, in spite of current standard of care, many people with diabetes continue to have persistent lipid abnormalities resulting in high residual CV risk.

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Adding Praluent (Alirocumab) To Statins Reduces LDL in High Cardiovascular Risk Diabetics

MedicalResearch.com Interview with:

Lawrence Leiter, M.D. MDCM, FRCPC, FACP, FACE, FAHA Chair of the ODYSSEY DM Steering Committee and Director of the Lipid Clinic at the Li Ka Shing Knowledge Institute St. Michael’s Hospital University of Toronto, Canada

Dr. Lawrence Leiter

Lawrence Leiter, M.D. MDCM, FRCPC, FACP FACE, FAHA
Chair of the ODYSSEY DM Steering Committee and
Director of the Lipid Clinic at the Li Ka Shing Knowledge Institute
St. Michael’s Hospital
University of Toronto, Canada

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The ODYSSEY DM-INSULIN trial was a randomized, double-blind, placebo-controlled, multicenter study that evaluated alirocumab (Praluent) in 517 patients with insulin treated type 1 and type 2 diabetes with high cardiovascular (CV) risk and hypercholesterolemia despite maximally tolerated dose (MTD) statins. The primary endpoint was percent change in calculated LDL-C from baseline to week 24.

Alirocumab 75 mg every two weeks was added to MTD statins, with the dose increased at week 12 to 150 mg every two weeks if the LDL-C at week 8 was greater than or equal to 70 mg/dL. In fact, only about 20% of the alirocumab treated participants required the higher dose.

Results of the type 2 diabetes study population (n=441) showed that the addition of alirocumab to MTD statin therapy, reduced LDL-C by 48.2 percent from baseline compared to a 0.8 percent increase for placebo. The mean difference between the two treatment arms was -49 percent (p<0.0001). Treatment with alirocumab also improved the overall lipid profile. Furthermore, no new safety issues were identified.

There is a large unmet need for improving cholesterol lowering in patients with diabetes. Despite current standard of care, nearly 70 percent of people age 65 or older with diabetes die from some form of heart disease; and 16 percent die of stroke. Additionally, in spite of current standard of care, many people with diabetes continue to have persistent lipid abnormalities resulting in high residual CV risk.

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Cholesterol Uptake Capacity, a New Indicator of HDL Functionality, for Cardiovascular Risk Stratification in the Real World.

MedicalResearch.com Interview with:
Amane Harada, PhD
Senior Researcher
Central Research Laboratories, Sysmex Corporation
Kobe, Japan

Ryuji Toh, MD, PhD Associate Professor Division of Evidence-based Laboratory Medicine Kobe University Graduate School of MedicineRyuji Toh, MD, PhD
Associate Professor
Division of Evidence-based Laboratory Medicine
Kobe University Graduate School of Medicine
Kobe, Japan 


MedicalResearch.com: What is the background for this study?

Response: High-density lipoprotein (HDL) exhibits a variety of anti-atherogenic functions including anti-inflammatory and anti-oxidative functions as well as promoting reverse cholesterol transport. However, it has been reported that HDL may lose its anti-atherogenic properties and become “dysfunctional” HDL under pathological conditions.

Recent studies have demonstrated that cholesterol efflux capacity of HDL is a better predictor of CVD than HDL-C, suggesting that not only the quantity, but also the quality of HDL may significantly modulate and predict the progression of cardiovascular disease.

However, the conventional procedure for efflux capacity assay requires radiolabeling and cells, and the procedures are time consuming. Therefore, its clinical application is impractical.

To solve those problems, we have recently developed a new assay system to evaluate the capacity of HDL to accept cholesterol, named “uptake capacity”.

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Improving Statin Adherence Would Reduce Need For Expensive PCSK9 Inhibitors

MedicalResearch.com Interview with:
Julia M. Akeroyd, MPH

Center for Innovations in Quality, Effectiveness, and Safety (IQuESt)
Michael E. DeBakey Veteran Affairs Medical Center
Salim S Virani, MBBS, Ph.D.
Baylor College of Medicine

MedicalResearch.com: What is the background for this study?

Response: In the recently published Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial, treatment with evolocumab resulted in a 15% relative (1.5% absolute) risk reduction of major cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD) at a median follow-up of 2.2 years. Given the high cost of evolocumab, there is a need to identify what proportion of ASCVD patients would qualify for evolocumab based on FOURIER entry criteria and how eligibility would change if maximal doses of evidence-based lipid lowering therapies were required.

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Many Eligible Groups Not Receiving Recommended Statin Therapy

MedicalResearch.com Interview with:
Dr. Yashashwi Pokharel MD, MSCR
Department of Cardiovascular Research
Saint Luke’s Mid-America Heart Institute
Kansas City, Missouri and
Salim S. Virani, MD PhD, FACC, FAHA
Associate Professor, Section of Cardiovascular Research
Associate Director for Research, Cardiology Fellowship Training Program
Baylor College of Medicine
Investigator, Health Policy, Quality and Informatics Program
Michael E. DeBakey Veterans Affairs Medical Center HSR&D Center of Innovation
Staff Cardiologist, Michael E. DeBakey Veterans Affairs Medical Center
Houston, TX

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Unlike the previous cholesterol management guideline that recommended use of either statin and non-statin therapy to achieve low density lipoprotein cholesterol (LDL-C) target, the 2013 American College of Cardiology/American Heart Association cholesterol management guideline made a major paradigm shift by recommending statin focused treatment in 4 specific patient groups and replaced LDL-C target with fixed statin intensity treatment (moderate to high intensity statin therapy).

With this change, it was speculated that a large number of patients would be eligible for statin treatment (in one study, up to 11.1% additional patients were expected to be eligible for statin therapy). Our study provided the real world trends in the use of statin and non-statin lipid lowering therapy (LLT) from a national sample of cardiology practices in 1.1 million patients 14 months before and 14 months after the release of the 2013 guideline.

We found a modest, but significant increasing trend in the use of statin therapy in only 1 of the 4 patient groups eligible for statin therapy (i.e., 4.3% increase in the use of moderate to high intensity statin therapy in patients with established atherosclerotic cardiovascular disease). We did not find any significant change in non-statin LLT use. Importantly, about a third to half of patients in statin eligible groups were not receiving moderate to high intensity statin therapy even after the publication of the 2013 guideline.

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PCSK9 Inhibition with Alirocumab Increases Removal of LDL Cholesterol

MedicalResearch.com Interview with:
Henry N. Ginsberg, MD

Irving Institute for Clinical and Translational Research
Columbia University
Columbia College of Physicians and Surgeons
New York, NY

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Previous studies in mice and cells have identified increased hepatic low density lipoprotein (LDL) receptors as the basis for LDL lowering by PCSK9 inhibitors, but there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoprotein metabolism, particularly effects on very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL) or LDL metabolism.

This study in 18 healthy subjects, found that alirocumab decreased the number of IDL and LDL particles in the circulation, and their associated cholesterol and apoB levels by increasing efficiency of the clearance of IDL and LDL. There were not effects on VLDL metabolism. The increased clearance of IDL meant that less LDL was produced from IDL, which is the precursor of LDL. Thus, the dramatic reductions in LDL cholesterol resulted from both less LDL being produced and more efficient clearance of LDL. These results are consistent with increases in LDL receptors available to clear IDL and LDL from blood during PCSK9 inhibition.

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Meta-analysis of Long-Chain Omega-3 Fatty Acids and Coronary Heart Disease Risk

MedicalResearch.com Interview with:
Dominik D Alexander, PhD, MSPH

Principal Epidemiologist
EpidStat Institute
Ann Arbor, MI Seattle, WA

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: In recent years, the body of scientific literature on n-3 LCPUFA (EPA/DHA) intake and coronary heart disease (CHD) risk has exploded with mixed results. It was only logical to conduct a comprehensive meta-analysis of randomized controlled trials (RCTs) to estimate the effect of EPA+DHA on CHD, and to conduct a comprehensive meta-analysis of prospective cohort studies to estimate the association between EPA+DHA intake and CHD risk.

Among RCTs, there was a nonstatistically significant reduction in CHD risk with EPA+DHA
provision (SRRE=0.94; 95% CI, 0.85-1.05). Subgroup analyses of data from RCTs indicated a statistically significant CHD risk reduction with EPA+DHA provision among higher-risk populations, including participants with elevated triglyceride levels (SRRE=0.84; 95% CI, 0.72-0.98) and elevated low-density lipoprotein cholesterol (SRRE=0.86; 95% CI, 0.76-0.98). Meta-analysis of data from prospective cohort studies resulted in a statistically significant SRRE of 0.82 (95% CI, 0.74-0.92) for higher intakes of EPA+DHA and risk of any CHD event.

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Some Type 2 Diabetics May Benefit From Adding Fenofibrate To Statins

MedicalResearch.com Interview with:

Marshall B. Elam PhD MD Professor Pharmacology and Medicine (Cardiovascular Diseases) University of Tennessee Health Sciences Center Memphis

Dr. Marshall B. Elam

Marshall B. Elam PhD MD
Professor Pharmacology and Medicine
(Cardiovascular Diseases)
University of Tennessee Health Sciences Center
Memphis

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: This manuscript presents the findings of extended follow up of patients with Type 2 Diabetes who were treated with fenofibrate, a member of a group of triglyceride lowering medications known as fibrates or PPAR alpha agonists, as part of the Action to Control Cardiovascular Risk in T2DM (ACCORD) study.

ACCORD was designed to test the effect of intensive treatment of cardiovascular risk factors including blood glucose, blood pressure and lipids on risk of heart attack, stroke and cardiac death in patients with Type 2 Diabetes.

The lipid arm of ACCORD tested the hypothesis that adding fenofibrate to statin therapy would further reduce risk of these cardiovascular events.

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Familial Hypercholesterolemia Diagnosed Through EHR and Genetics Data

MedicalResearch.com Interview with:

Michael F. Murray MD Geisinger Health System Danville, PA 17822

Dr. Michael Murray

Michael F. Murray MD
Geisinger Health System
Danville, PA 17822

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The DiscovEHR cohort was formed as a result of a research collaboration between Geisinger Health System and Regeneron Pharmaceuticals. There are over 50,000 patient participants in the cohort who have volunteered to have their de-identified genomic sequence data linked to their de-identified EHR data for research purposes. We report in this paper findings around the identification of 229 individuals (1:256) with pathogenic or likely pathogenic variants in one of the three genes (LDLR, APOB, PCSK9) associated with Familial Hypercholesterolemia (FH). The study found that these individuals are unlikely to carry a diagnosis of FH and are at risk for early coronary artery disease.

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PCSK9 Inhibitor Praluent Substantially Reduced LDL-C Cholesterol

MedicalResearch.com Interview with:

Dr. Eli M. Roth MD, FACC President, Medical Director Sterling Research Group Cincinnati, OH

Dr. Eli Roth

Dr. Eli M. Roth MD, FACC
President, Medical Director
Sterling Research Group
Cincinnati, OH

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: At this year’s AHA 2016, we presented a pharmacodynamics analysis of ODYSSEY CHOICE I, which evaluated the effects of Praluent 300 mg administered every four weeks (Q4W) for 24 weeks in hypercholesterolemia patients at moderate to very high cardiovascular risk who were on maximally tolerated statin or no statin and/or other lipid-lowering therapies.

The pharmacodynamic analysis of CHOICE I in patients on statins supports the use of Praluent 300 mg Q4W as an alternative starting dose for patients who prefer a Q4W dosing regimen and demonstrates the value of LDL-C based dosing interval adjustment. The findings from this analysis were consistent with prior ODYSSEY Phase 3 studies, showing that Praluent substantially reduced circulating free PCSK9 concentration, resulting in significant LDL-C reductions. Additionally, Praluent was generally well tolerated.

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Byproduct of Sweet Potato Waste Offers Clue To Lipid Metabolism

MedicalResearch.com Interview with:
Dr. Koji Ishiguro

National Agriculture and Food Research Organization
Japan

MedicalResearch.com: What is the background for this study?

Response: -Sweet potato (Ipomoea batatas L.) roots are not only used for human consumption, they are used to make starch materials, processed foods, and distilled spirits in Japan. Starch use accounts for about 15% (131,500 tons) of total sweet potato production. Starch residues are discharged during starch production and are mainly used in animal feed and compost. Large amounts of the wastewater, which can cause serious environmental problems, are discarded after clarification. Investigation into the uses of the by-products of the sweet potato starch industry would benefit both the environment and industry.

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High Intensity Statins Increase For High Risk Atherosclerotic Patients, But Lagging in Women and Minorities

MedicalResearch.com Interview with:

Fatima Rodriguez, MD, MPH Division of Cardiovascular Medicine and Cardiovascular Institute Stanford University Stanford, CA

Dr. Fatima Rodriguez

Fatima Rodriguez, MD, MPH
Division of Cardiovascular Medicine and Cardiovascular Institute
Stanford University
Stanford, CA

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The 2013 ACC/AHA cholesterol management guidelines emphasized that high-risk patients with atherosclerotic disease should be on high-intensity statins. We sought to determine how these guidelines are being adopted at the Veterans Affairs (VA) Health System and to identify treatment gaps.

Our main findings were that the use of high-intensity statins increased from 23 to 35% following the guideline release for these high-risk patients. However, high-intensity statin use was lowest in Hispanics and Native Americans. Women, older adults, and patients with peripheral arterial and cerebrovascular disease were also less likely to undergo statin intensification after the release of the guideline. We also noted geographic and institutional differences across VA hospitals in rates of high-intensity statin use for secondary prevention.

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Americans Continue To Have Better Lipid Profiles

MedicalResearch.com Interview with:
Asher Rosinger, PHD, MPH
Epidemic Intelligence Service Officer, Centers for Disease Control and Prevention
Division of Health and Examination Nutrition Examination Surveys, Analysis Branch
National Center for Health Statistic

MedicalResearch.com: What is the background for this study?

Response: Total cholesterol, triglycerides, and low-density lipoprotein (LDL) levels are linked to coronary heart disease and cardiovascular events. Between 1999 and 2010, total cholesterol, triglycerides, and LDL levels declined among U.S. adults. We used new data from the 2011-2014 nationally representative National Health and Nutrition Examination Survey (NHANES) to determine if earlier trends continued.

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Cardioprotective Effect of PCSK9 Inhibitors Should Outweigh Potential Harm of Diabetes Risk

MedicalResearch.com Interview with:
Brian A. Ference, M.D
Division of Cardiovascular Medicine
Wayne State University School of Medicine
Detroit, MI

MedicalResearch.com: What are the main findings?

Response: Lifelong exposure to modestly lower plasma LDL-C levels caused by rare loss-of-function mutations in the PCSK9 gene is associated with a substantially lower lifetime risk of developing cardiovascular disease. This discovery motivated the development of monoclonal antibodies directed against PCSK9 which have now been shown to reduce plasma LDL-C levels by 50-60%. The cardiovascular medicine community is early anticipating the results of two large cardiovascular outcome trials that will determine if lowering LDL-C levels by inhibiting PCSK9 will reduce the risk of cardiovascular events.

Because monoclonal antibodies and other therapies directed against PCSK9 are designed to recapitulate the phenotype of PCSK9 loss-of-function mutations, we reasoned that it may be possible to anticipate the efficacy and safety results of the ongoing cardiovascular outcome studies by more precisely characterizing the effect of genetic variants in the PCSK9 gene on the risk of both cardiovascular events and new onset diabetes.

To do this, we a constructed genetic score consisting of multiple independently inherited variants in the PCK9 gene to create an instrument that mimics the effect of PCSK9 inhibitors. We then compared the effect of genetic variants that mimic the effect of PCSK9 inhibitors with the effect of genetic variants in the HMGCR gene that mimic the effect of statins to make inferences about the likely effect of PCSK9 inhibitors on the risk of cardiovascular events and new onset diabetes as compared to treatment with a statin.

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Phase1 Trial Supports PCSK9-Inhibitor Inclisiran For Reducing LDL Cholesterol

MedicalResearch.com Interview with:

Kevin Fitzgerald, Ph.D. Alnylam Pharmaceuticals Cambridge, MA 02142

Dr. Kevin Fitzgerald

Kevin Fitzgerald, Ph.D.
Alnylam Pharmaceuticals
Cambridge, MA 02142

MedicalResearch.com: What is the background for this study?

Response: Inclisiran (ALN-PCSsc) is a subcutaneously administered RNAi therapeutic targeting PCSK9 in development for the treatment of hypercholesterolemia. The Phase 1 trial of inclisiran was conducted in the U.K. as a randomized, single-blind, placebo controlled, single ascending-and multi-dose, subcutaneous dose-escalation study in 69 volunteer subjects with elevated baseline LDL-C (≥ 100 mg/dL). The primary objective of the study was to evaluate the safety, side effect profile, and pharmacodynamics effects of inclisiran.

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Hypertriglyceridemia Markedly Increases Risk of Acute Pancreatitis

MedicalResearch.com Interview with:
Borge G. Nordestgaard, MD, DMSc

Professor, University of Copenhagen
Chief Physician, Dept. Clinical Biochemistry, Herlev and Gentofte Hospital
Copenhagen University Hospital
Herlev, Denmark

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Acute pancreatitis is an inflammatory disorder of the pancreas with gallstones and high-alcohol consumption as leading risk factors, while mild-to-moderately increased plasma triglycerides hitherto has been overlooked. We surprisingly found that the risk of developing acute pancreatitis was increased already from triglycerides of 175 mg/dL (2 mmol/L) and above. When triglycerides were above 443mg/dL (5mmol/L) the risk was increased a massive 9-fold. Interestingly, this risk was higher than the corresponding 3.4-fold higher risk for myocardial infarction.

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Systematic Review Finds PCSK9 Inhibitors Reduce LDL-C and Are Well Tolerated

MedicalResearch.com Interview with:

Prof. Dr. Ioana Gouni-Berthold MD

Dr. Gouni Gerthold

Prof. Dr. Ioana Gouni-Berthold MD
Center for Endocrinology, Diabetes and Preventive Medicine (ZEDP)
University of Cologne
Cologne, Germany

MedicalResearch.com: What is the background for this study?

Response: In Europe, up to half of the population aged between 35 and 64 has hypercholesterolemia (high levels of low-density lipoprotein cholesterol [LDL-C]), putting them at risk of heart disease. Despite increased treatment rates in recent years, many patients still do not receive adequate therapy, and heart disease remains the biggest cause of death in the USA and most European countries.

Two drugs, alirocumab and evolocumab, have recently been approved for lowering LDL-C in patients with hypercholesterolaemia as an ‘add-on’ therapy to other lipid-lowering medication, or for use alone in patients unable to tolerate statins. These drugs have a unique mode of action– they inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that binds to LDL receptors and targets them for degradation. In the absence of PCSK9, the LDL receptor recycling is restored and the receptors are able to remove LDL from the blood.

Both alirocumab and evolocumab have been tested in numerous patient populations in phase 3 trials; albeit evolocumab has an additional indication of homozygous familial hypercholesterolemia. We therefore felt that there was a need to collate the available data to assess the efficacy and safety of each agent. We chose reduction in LDL-C as our outcome of interest, because this was the primary endpoint of the pivotal clinical trials.

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Linoleic Acid (Omega-6) in Fatty Tissue Linked To Lower Mortality

MedicalResearch.com Interview with:

David Iggman, MD, PhD Unit for Clinical Nutrition and Metabolism Department of Public Health and Caring Sciences Uppsala University, Uppsala Center for Clinical Research Dalarna Falun, Sweden

Dr. David Iggman

David Iggman, MD, PhD
Unit for Clinical Nutrition and Metabolism
Department of Public Health and Caring Sciences
Uppsala University, Uppsala
Center for Clinical Research Dalarna
Falun, Sweden

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: There is some controversy regarding which dietary fats are preferable and in what amounts, not least regarding the polyunsaturated fats. It is also challenging to adequately assess peoples intakes of dietary fats.

The main findings of this study was that among fatty acids in the body (reflecting the intake during the last year or so), linoleic acid (omega-6) was associated with lower mortality in 71-year-old men with 15 years follow-up.

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Not Enough Evidence To Recommend For or Against Cholesterol Screening In Children and Teens

MedicalResearch.com Interview with:

Dr. David Grossman M.D., M.P.H. Vice chair of the U.S. Preventive Services Task Force and Professor at the University of Washington Schools of Public Health and Medicine

Dr. David Grossman

Dr. David Grossman M.D., M.P.H.
Vice chair of the U.S. Preventive Services Task Force and
Professor at the University of Washington Schools of Public Health and Medicine

MedicalResearch.com: What is the background for this recommendation?

Response: The Task Force recognizes the importance of cardiovascular health for young people. Children and adolescents with high cholesterol are more likely to become adults with high cholesterol, and high cholesterol in adulthood can lead to serious health outcomes such as heart attacks and strokes. However, when the Task Force reviewed evidence for cholesterol screening in children and adolescents without any signs or symptoms, we found that there is not enough evidence to recommend for or against screening. In the face of unclear evidence, the Task Force is calling on the research community to prioritize studies on screening and treatment of lipid disorders in children and teens to help us all learn more about the impact that screening at an early age may have on the cardiovascular health of adults.

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Too Much ‘Good Cholesterol’ HDL Can Also Be A Bad Thing

MedicalResearch.com Interview with:

Ziyad Al-Aly, MD, FASN Assistant Professor of Medicine Washington University School of Medicine Co-Director, Clinical Epidemiology Center Associate Chief of Staff for Research and Education Veterans Affairs Saint Louis Health Care System

Dr. Ziyad Al-Aly

Ziyad Al-Aly, MD, FASN
Assistant Professor of Medicine
Washington University School of Medicine
Co-Director, Clinical Epidemiology Center
Associate Chief of Staff for Research and Education
Veterans Affairs Saint Louis Health Care System

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: I think the most important, and novel finding is that elevated levels of HDL-cholesterol (which is thought of as the good cholesterol) are associated with increased risk of death. Previously it was thought that high HDL (increased good cholesterol) is a good thing.

We used Big Data approach (over 16 million person-years; 1.7 million people followed for over 9 years) to evaluate the relationship between HDL-Cholesterol (the good cholesterol) and risk of death. We found that low HDL is associated with increased risk of death (which is expected and consistent with prior knowledge). The novel and unexpected finding is the observation that high HDL-Cholesterol is also associated with increased risk of death. The relationship between HDL-Cholesterol levels and risk of death is a U-shaped curve where risk is increased at both ends of the HDL-C values spectrum (at both low and high end); Too low and too high is associated with higher risk of death. The findings may explain why clinical trials aimed at increasing HDL-Cholesterol levels failed to show improvement of clinical outcomes.

This finding was not expected, and has not been reported previously in large epidemiologic studies such as Framingham Heart Study and others. The Framingham Heart study and others significantly advanced our understanding of the relationship between cholesterol parameters (including HDL-Cholesterol) and clinical outcomes. However, these studies are limited in that the number of patients in these cohorts was several thousands which is relatively small compared to what a Big Data approach (millions of patients) enables us to see. Big Data approach allows a more nuanced (a more detailed) examination of the relationship between HDL and risk of death across the full spectrum of HDL levels.

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US Task Force Reviews Lipid Screening For Children and Adolscents

MedicalResearch.com Interview with:

Paula Lozano, MD MPH Associate Medical Director, Research and Translation Group Health Physicians SENIOR INVESTIGATOR Group Health Research Institute Metropolitan Park East Seattle, WA 98101

Dr. Paula Lozano

Paula Lozano, MD MPH
Associate Medical Director, Research and Translation
Group Health Physicians
Senior Investigator
Group Health Research Institute
Metropolitan Park East
Seattle, WA 98101

MedicalResearch.com: What is the background for this study?

Response: This wasn’t a study, but rather a study of studies, to support the US Preventive Services Task Force in updating its previous recommendation of

I: insufficient to assess the balance of benefits and harms. We conducted two systematic evidence reviews of screening children and adolescents:

1. for familial hypercholesterolemia (FH, a genetic disorder that interferes with the body’s ability to metabolize cholesterol and can result in early coronary heart disease); and

2. for multifactorial dyslipidemia—which we defined as elevated LDL cholesterol or total cholesterol, not caused by familial hypercholesterolemia. LDL and total cholesterol were of interest because they are considered atherogenic.

One of the challenges of lipid screening in youth is that blood levels of these atherogenic lipids are known to fluctuate during the course of childhood and adolescence. It’s sort of a W-shaped curve, with a peak at age 9-11 years. So for a given child, the definition of what’s an elevated LDL or total cholesterol level will change with age. Also, two-thirds of kids identified as having high cholesterol through universal screening would not go on to have high cholesterol as adults.

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Study Evaluates Effects of Polyunsaturated Fats on Development of Diabetes

MedicalResearch.com Interview with:

Dr. Fumiaki Imamura Ph.D. MRC Epidemiology Unit University of Cambridge

Dr. Fumiaki Imamura

Dr. Fumiaki Imamura Ph.D.
MRC Epidemiology Unit
University of Cambridge

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: There was insufficient evidence for effects of polyunsaturated fatty acids (PUFA) intake or blood biomarkers on the development of type 2 diabetes. For instance, previous studies using PUFA biomarkers had a maximum of only 673 type 2 diabetes cases. In the EPIC-InterAct Study – a large European collaborative, prospective study where 12,132 diabetes cases were ascertained during its follow-up – we found diverse associations of blood levels of different types of PUFAs with incidence of type 2 diabetes.

Despite this diversity, clinically relevant results were observed for major polyunsaturated fatty acids. Higher blood levels of total omega-6 PUFAs and the major omega-6 PUFA (linolenic acid) were associated with a lower risk of developing type 2 diabetes. Likewise, levels of alpha linolenic acid, known as a plant-origin omega-3 PUFA, were associated with lower type 2 diabetes risk. Marine-origin omega-3 PUFAs, including docosahexaenoic acid (DHA), showed inconsistent associations with type 2 diabetes risk.

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Niacin-Laropiprant Reduced Quality of Life-Adjusted Survival and Increased Hospital Costs in HPS2-THRIVE

MedicalResearch.com Interview with:
Seamus Kent, MSc, Research Fellow and
Borislava Mihaylova, MSc DPhil, Associate Professor
Health Economics Research Centre,
Nuffield Department of Population Health
University of Oxford, UK

MedicalResearch.com: What is the background for this study?

Response: Niacin lowers the LDL cholesterol and increases the HDL cholesterol and it was hoped this would translate into reduced risks of vascular events. This hypothesis was assessed in the Heart Protection Study 2 – Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial in which over 25,000 adults aged 50 to 80 years with prior cardiovascular disease were randomised to either niacin-laropiprant or placebo, in addition to effective LDL-cholesterol lowering therapy, and followed for about 4 years. Previously published results from the study demonstrated that niacin-laropiprant did not significantly reduce the risk of major vascular events but did significantly increase the risk of various adverse events including infections, bleeding, gastrointestinal, musculoskeletal, skin, and diabetes-related events.

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Statins Reduces But Don’t Eliminate Risk of CAD In Familial Hypercholesterolemia

MedicalResearch.com Interview with:
Joost Besseling, PhD-student

Academic Medical Center
Dept. of Vascular Medicine
Amsterdam

MedicalResearch.com: What is the background for this study? 

Response: It was unkown to what extent statin therapy reduces the risk for coronary artery disease and mortality in patients with heterozygous familial hypercholesterolemia (FH). One previous study found that the relative risk reduction was 76%, but the study population in this study consisted of with a very severe FH phenotype. This result is therefore an overestimation of the risk reduction in the general heterozygous familial hypercholesterolemia population.

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Familial Hypercholesterolemia, Widely Under-Diagnosed, Raises Risk of Atherosclerotic Cardiovascular Disease

MedicalResearch.com Interview with:

Amanda M. Perak, MD Division of Cardiology, Ann & Robert H. Lurie Children’s Hospital of Chicago, and Department of Preventive Medicine Northwestern University Feinberg School of Medicine

Dr. Perak

Amanda M. Perak, MD
Division of Cardiology, Ann & Robert H. Lurie Children’s Hospital of Chicago, and
Department of Preventive Medicine
Northwestern University Feinberg School of Medicine

Donald M Lloyd-Jones, MD/ScM (senior author)
Senior Associate Dean for Clinical and Translational Research; Chair, Department of Preventive Medicine
Director, Northwestern University Clinical and Translational Sciences Institute (NUCATS) and Eileen M. Foell Professor
Professor in Preventive Medicine-Epidemiology and Medicine-Cardiology

MedicalResearch.com: What is the background for this study?

Response: Heterozygous familial hypercholesterolemia, or FH, affects up to 1 in 200 individuals in the United States. FH is a genetic disorder that should be suspected in individuals with very high levels of low-density lipoprotein cholesterol (LDL-C; at least 190 mg/dL) plus a first-degree relative with similar degree of high cholesterol or with premature coronary heart disease. Individuals with FH are exposed to high levels of “bad” cholesterol from birth, so if they are not treated with cholesterol-lowering therapy, they are at elevated risk for atherosclerotic cardiovascular disease (ASCVD; diseases related to hardening of the arteries, including heart attack and stroke). However, these risks previously had not been well quantified in untreated individuals with familial hypercholesterolemia in the general US population.

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Large Harvard Study Confirms Health Benefits of Unsaturated Fats

MedicalResearch.com Interview with:

Daniel (Dong) Wang, MD, ScD, Research Fellow Department of Nutrition | Harvard T.H. Chan School of Public Health Boston, MA 02115

Dr. Wang

Daniel (Dong) Wang, MD, ScD, Research Fellow
Department of Nutrition | Harvard T.H. Chan School of Public Health
Boston, MA 02115

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: There has been widespread confusion in the biomedical community and the general public about the health effects of specific types of fat in the diet. In particular, the role of unsaturated fats vs. saturated fat in cardiovascular disease prevention remains controversial. Our study is by far the most detailed and powerful examination of this very important research topic, i.e., health effects of specific types of dietary fats, because of very large sample size (more than 120,000 men and women), repeated and validated measurements of diet and lifestyle over an extended follow-up (up to 32 years). In addition, our study is able to examine a much broader range of outcomes, including total mortality and mortality due to cardiovascular disease, cancer, neurodegenerative disease and respiratory disease.

We found that different types of dietary fat had different associations with mortality. Consuming higher amounts of unsaturated fats- mainly from plant-based foods like olive oil, canola oil, soybean oil and nuts – was associated with lower mortality, while higher consumption of saturated-found in red meat, butter, cheese, and ice cream- and trans fats- predominantly from hydrogenated oils- was linked with higher mortality compared with the same number of calories from carbohydrates. Most importantly, replacing saturated fats with unsaturated fats conferred substantial health benefits, including lowering risk of all-cause premature death and premature death due to cardiovascular disease, cancer, neurodegenerative disease and respiratory disease.

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HDL May Be Overrated as Independent Risk Factor for Heart Disease

MedicalResearch.com Interview with:

Michael Miller, MD, FACC, FAHA Professor of Cardiovascular Medicine, Epidemiology & Public Health University of Maryland School of Medicine Staff Physician, Baltimore VAMC Director, Center for Preventive Cardiology University of Maryland Medical Center Baltimore, Maryland

Dr. Michael Miller

Michael Miller, MD, FACC, FAHA
Professor of Cardiovascular Medicine, Epidemiology & Public Health
University of Maryland School of Medicine
Staff Physician, Baltimore VAMC
Director, Center for Preventive Cardiology
University of Maryland Medical Center
Baltimore, Maryland

MedicalResearch.com: What is the background for this study?
Dr. Miller: It has become an article of faith that HDL (the good cholesterol) is an independent risk factor for heart disease. However, previous studies did not examine the importance of HDL after accounting for both LDL (bad cholesterol) and triglycerides (blood fats).  This is important because HDL is associated with LDL and triglycerides. We hypothesized that if HDL is truly an independent risk factor, then low HDL levels in isolation would continue to be linked to an increased risk of heart disease while high HDL levels would continue to protect the heart even if LDL and triglycerides levels were elevated.

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Not All Patients Require High Intensity Statins To Achieve LDL Control

MedicalResearch.com Interview with:

Martha M. Rumore, PharmD, JD, MS, LLM, FAPhA Associate Professor, Social, Behavioral & Administrative Pharmacy Touro College of Pharmacy New York, NY 10027 & Of Counsel Sorell, Lenna, & Schmidt, LLP

Dr. Martha Rumore

Martha M. Rumore, PharmD, JD, MS, LLM, FAPhA
Associate Professor, Social, Behavioral & Administrative Pharmacy
Touro College of Pharmacy
New York, NY 10027
& Of Counsel Sorell, Lenna, & Schmidt, LLP

MedicalResearch.com: What is the background for this study?

Dr. Rumore: The management of lipid therapy is only one component that affects overall cardiovascular outcomes.This study is one of the first to look at the benefits of dose titration versus intensity-based statin therapy.  To evaluate whether patients titrated on statin therapy using ATPIII algorithm with an LDL goal of <100mg/dL also met the 2013 ACC/AHA Guideline for Management of Blood Cholesterol goal of ≥40% LDL reduction from baseline compared to inpatients initiated on high-moderate intensity statin (HIS).  Other objectives included comparison of algorithms to lower LDL ≥40%, final dose, adverse drug events (ADEs), clinic visits to goal, and cardiovascular event occurrence.

MedicalResearch.com: What are the main findings?

Dr. Rumore: 981 patients were included- 43% were titrated and 57% achieved LDL<100; 38% achieved both LDL <100mg/dL and LDL ≥40% reduction; 58% received HIS and 53% achieved LDL <100; 43% achieved both LDL <100mg/dL and LDL ≥40% reduction.

Initiating patients on  High Intensity statins was not more effective than dose titration in achieving <100mg/dL and ≥40% LDL reduction;X2=0.006,N=159,p=0.938. A 50% LDL reduction in patients that also achieved an LDL <100 was 54% and 48%, in titration and HIS groups, respectively; X2=0.611,N=159,p=0.434.  The titration group required an average of 4.3 clinic visits to achieve goal, compared to 3.1 visits for HIS; p=0.309; 95% CI(-1.36,1.06).

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PCSK9 Antibody May Revolutionize Treatment of Atherosclerosis and Acute Coronary Syndrome

MedicalResearch.com Interview with:

Paul A. Gurbel, M.D. Director, Inova Center for Thrombosis Research and Drug Development Director, Cardiovascular Medicine Research Director, Interventional Cardiology Inova Heart and Vascular Institute Falls Church, VA Professor of Medicine, Johns Hopkins University School of Medicine Adjunct Professor of Medicine, Duke University School of Medicine

Dr. Paul Gurbel

Paul A. Gurbel, M.D.
Director, Inova Center for Thrombosis Research and Drug Development
Director, Cardiovascular Medicine Research
Director, Interventional Cardiology
Inova Heart and Vascular Institute
Falls Church, VA
Professor of Medicine,
Johns Hopkins University School of Medicine
Adjunct Professor of Medicine,
Duke University School of Medicine 

MedicalResearch.com: What is the background for this review? What are the main findings?

Dr. Gurbel: In current practice, treatment with statins and antiplatelet agents is the primary strategy to reduce death and ischemic cardiovascular events following ACS (acute coronary syndrome)/PCI. Immediately following ACS, many patients are incompletely responsive to potent current therapy and remain at high risk for recurrent thrombotic events. Treatment with monoclonal antibodies that target proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new potent lipid lowering therapy. Recent studies have shown that PCSK9 antibodies combined with statins provided marked additional benefits in reducing atherogenic lipid fractions. In a recent meta-analysis, PCSK9 antibody therapy was also associated with a reduction in mortality and no increase in serious adverse events. In the current Narrative Review, we focused on novel pathways affected by PCSK9 antibodies that may make them appropriate for immediate treatment in patients with acute coronary syndrome.

MedicalResearch.com: What are the main findings?

Dr. Gurbel: PCSK9 antibodies, in addition to markedly reducing LDL levels, may also reduce pro-inflammatory oxidized LDL levels and platelet function. The latter properties, in addition to plaque stabilization, may provide antithrombotic properties favorably influencing clinical outcomes following acute administration at the time of  acute coronary syndrome.

MedicalResearch.com: What should clinicians and patients take away from your report?

Dr. Gurbel: In addition to a potent lipid lowering effect, PCSK9 antibody therapy when administered immediately at the time of acute coronary syndrome in addition to standard statin and antiplatelet therapy may provide additional antithrombotic effects. The latter novel properties of PCSK9 antibodies may be associated with improved patient outcomes. However, at this time there is no direct evidence for recommending PCSK9 antibody therapy in patients at the time of presentation with acute coronary syndrome .

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Dr. Gurbel: A large scale randomized study assessing the clinical effects of PCSK9 antibody therapy on top of current statin and antiplatelet therapy is needed. In addition, mechanistic studies to further delineate anti-inflammatory and antithrombotic effects of PCSK9 antibody therapy are also needed.

MedicalResearch.com: Is there anything else you would like to add?

Dr. Gurbel: PCSK9 antibody therapy provides marked lowering of LDL. The latter property may revolutionize the treatment of patients with atherosclerosis. The potential antithrombotic effects of PCSK9 antibody therapy, in turn, may revolutionize acute therapy of ACS. 

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:

Navarese EP, Kołodziejczak M, Kereiakes DJ, Tantry US, O’Connor C, Gurbel PA. Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies for Acute Coronary Syndrome: A Narrative Review. Ann Intern Med. [Epub ahead of print 22 March 2016] doi:10.7326/M15-2994

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

More Medical Research Interviews on MedicalResearch.com

Dr. Paul Gurbel (2016). PCSK9 Antibody May Revolutionize Treatment of Atherosclerosis and Acute Coronary Syndrome MedicalResearch.com

Familial Hypercholesterolemia Likely Underrecognized

MedicalResearch.com Interview with:

Dr. Sarah de Ferranti MD MPH Boston Children’s Hospital Director, Preventive Cardiology Program Assistant Professor of Pediatrics Harvard Medical School

Dr. Sarah de Ferranti

Dr. Sarah de Ferranti MD MPH
Boston Children’s Hospital
Director, Preventive Cardiology Program
Assistant Professor of Pediatrics
Harvard Medical School

MedicalResearch.com:  What are the main findings?

Dr. de Ferranti: Familial hypercholesterolemia, or FH, is a genetic condition that causes severely elevated cholesterol levels from birth and is a leading cause of early heart attack. It is generally slowly progressive without symptoms until there is serious heart disease in the 3rd and 4th decade of life, making it important to look for it at a young age. Prior to this analysis it was thought that FH affected about 1 in 500 adults. The current study used data from 36,949 adults who took part in the 1999-2012 National Health and Nutrition Examination Survey (NHANES) and extrapolated to the 210 million U.S. adults aged 20 years and older. We identified cases of probably or definite Familial hypercholesterolemia in our analysis by using a combination of high levels of low-density-lipoprotein cholesterol (considered “bad” because it contributes to plaque buildup in arteries) and early heart disease in a person or close relative.

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With Appropriate Dose and Formulation, Niacin Can Be Lipid Lowering and Cardioprotective

MedicalResearch.com Interview with:

Dr. Richard L. Dunbar MD MS Assistant Professor of Medicine, Attending Physician, Preventive Cardiovascular Medicine Clinic, Member, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of MedicineMember, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine

Dr. Richard Dunbar

Dr. Richard L. Dunbar MD MS
Assistant Professor of Medicine, Attending Physician, Preventive Cardiovascular Medicine Clinic, Member, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of MedicineMember, Institute for Diabetes, Obesity and Metabolism,
University of Pennsylvania School of Medicine and

Dr. Harsh Goel WellSpan Academic Hospitalists Department of Medicine, York Hospital, PA

Dr. Harsh Goel

Dr. Harsh Goel
WellSpan Academic Hospitalists
Department of Medicine, York Hospital, PA 

MedicalResearch.com: What is the background for this analysis?

Response: Niacin is the first cholesterol lowering treatment to prevent heart attacks and lower long term mortality. It thus provided the first proof that lowering cholesterol reduces cardiovascular risk. However, it is generally poorly tolerated due to almost universal flushing, limiting use. The better-tolerated statin drugs overshadowed niacin, rightly dominating hyperlipidemia therapy. Despite their advantages, statins are far from perfect, leaving important gaps. Firstly, at least 10% of patients simply don’t tolerate statins. Secondly, about 40% of patients have insufficient cholesterol lowering, leaving them far from their target LDL-cholesterol levels. Finally, even though statins lower cardiovascular risk, they by no means eliminate it and significant residual risk remains even in patients who respond to them.

The relatively poor tolerance of niacin motivated development of an extended-release alternative which was dosed very differently from the established cardioprotective regimen used in the Coronary Drug Project (CDP) and the Stockholm Ischemic Heart Disease Study (SIHDS), the two landmark trials that proved niacin’s benefits. These trailblazing trials used 3 grams of niacin divided throughout the fed portion of the day as 1 gram thrice daily with meals. In sharp contrast, the alternative regimen was severely handicapped by a profoundly lower dose of only 2 grams per day. Perhaps worse, the alternative regimen dosed all of the niacin at one sitting, at bedtime before the overnight fast, rather than three times a day before meals. We believe these were critical departures from the established cardioprotective niacin regimen, insofar as they severely undermined the alternative regimen’s efficacy. Accordingly, when added to statins, the alternative regimen failed to recapitulate the benefits seen with the established cardioprotective regimen in two recent large clinical trials, the AIM-HIGH trial and the HPS2-THRIVE trial. Besides the inherent flaws of the alternative regimen, there were also major issues with the trial designs which likely contributed to null results.

From a practice standpoint, this is worrisome, because clinicians may draw erroneous conclusions from the trials of the alternative regimen, and thereby deny a significant population of hyperlipidemic patients the benefits of a well-proven cardioprotective therapy, i.e. the population which does not tolerate or does not respond adequately to statins (almost 50% of at risk patients). Hence, we embarked on a critical analysis and review of the alternative regimen with a special focus on the AIM-HIGH and HPS2-THRIVE trials to bring to light the pitfalls of comparing radically different regimens of what is nominally the same drug.

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Biomarker CRP Correlates With Coronary Plaque In STEMI Patients on Statins

MedicalResearch.com Interview with:

Lorenz Räber, MD, PhD Director Division CAD and MI INSELSPITAL, Bern University Hospital Bern, Switzerland

Dr. Lorenz Räber

Lorenz Räber, MD, PhD
Director Division CAD and MI
INSELSPITAL, Bern University Hospital
Bern, Switzerland

Medical Research: What is the background for this study?

Response: Inflammation is a key player in the pathobiology of atheorsclerosis. Inflammatory markers and specifically C-reactive protein (CRP) associate with statin-mediated clinical event reduction and plaque burden reduction in patients with stable CAD. Whether CRP correlates with changes in plaque composition, ie. an important presumed substrate of plaque vulnerability, remains unknown. We thought to assess compositional atheroma changes by means of virtual histology IVUS in relation to levels of hs-CRP in STEMI patients. For this purpose, we performed intracoronary imaging using virtual histology IVUS in the proximal part of the two non-infarct related coronary arteries of STEMI patients at baseline and 13 months follow-up (IBIS-4 study). A total of 44 patients with 80 vessels had serial imaging and hsCRP measurements available.

Medical Research: What are the main findings?

Response: This is the first study to show that serial changes and on-treatment levels of hs-CRP correlate with virtual histology IVUS-defined necrotic core content in patients with STEMI receiving high-intensity statin therapy. Patients with a low inflammatory activity are more likely to achieve a reduction in necrotic core, which represents a presumed substrate of plaque vulnerability. These findings may provide the basis for assessing inflammation at follow-up to monitor disease activity in STEMI patients.

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Avocado Substituted Diets Improve Lipid Profile

MedicalResearch.com Interview with:

Sachin A. Shah, Pharm.D. Residency Director & Regional Coordinator - Travis AFB Associate Professor of Pharmacy Practice TJ Long School of Pharmacy and Health Sciences University of the Pacific

Avocado- Wikipedia image

Sachin A. Shah, Pharm.D.
Residency Director & Regional Coordinator –
Travis AFB
Associate Professor of Pharmacy Practice
TJ Long School of Pharmacy and Health Sciences
University of the Pacific

Medical Research: What is the background for this study? What are the main findings?

Dr. Shah: The link between serum cholesterol and cardiovascular mortality has been well established. Dietary sources of cholesterol can play a major role toward a beneficiary or unfavorable lipid profile. Fatty acids in foods typically fall within one of the four categories: saturated fats (SFAs), common in animal sources, trans fats (TFAs), common in processed foods, polyunsaturated fats (PUFAs), and monounsaturated fats (MUFAs), both common in plant-derived sources. Although low-fat diets are generally recommended, studies have indicated that altering the types of fats you consume may further modify the risk of dyslipidemia. We performed a meta-analysis of existing studies to determine the impact of avocados on the lipid profile.

Ten unique studies incorporating 229 subjects were included. Avocado consumption significantly reduced TC, LDL-C, and TG by 18.80 mg/dL, 16.50 mg/dL, 27.20 mg/dL respectively. HDL-C decreased non-significantly.

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Study Identifies Differences in Omega-6 vs Omega-3 in Brain Development

Noriko Osumi, DDS, PhD Director, Center for Neuroscience Professor, Department of Developmental Neuroscience Tohoku University School of Medicine Seiryo-machi, Aoba-ku, Sendai Japan

Dr. Noriko Osumi

More on Lipids on MedicalResearch.com
MedicalResearch.com Interview with:
Noriko Osumi, DDS, PhD
Director, Center for Neuroscience
Professor, Department of Developmental Neuroscience
Tohoku University School of Medicine
Seiryo-machi, Aoba-ku, Sendai Japan 

Medical Research: What is the background for this study? What are the main findings?
Dr. Osumi: Omega-6 and omega-3 fatty acids are known to be important for brain growth.

This is mainly because many researchers have shown that imbalance between these fatty acids during pregnancy causes several defects in future brain functions both in humans and rodents.

Therefore, we asked the underlying mechanism how maternal intake of the omega-6 excess/omega-3 deficient dietary impairs brain development in mice using genetical rescue and comprehensive lipidomics together with neural stem cell biology.

We have shown how these fatty acids affect brain growth, and revealed its molecular and cellular mechanisms.

In particular, the reduced thickness of the cortex is due to precocious gliogenesis following neurogenesis, which may include epoxide metabolites of omega-6 fatty acids.

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HDL Levels in Acute Coronary Syndrome May Reflect Inflammatory Response

Dr. Héctor González-Pacheco MD Coronary Care Unit, National Institute of Cardiology Mexico City, Mexico

Dr. González-Pacheco

MedicalResearch.com Interview with:
Dr. Héctor González-Pacheco MD

Coronary Care Unit, National Institute of Cardiology
Mexico City, Mexico

Medical Research: What is the background for this study?

Dr. González-Pacheco: Epidemiological studies have provided robust evidence for an inverse correlation between plasma levels of high-density lipoprotein cholesterol (HDL-C) and cardiovascular risk. At hospital admission, a high percentage of patients with an acute coronary syndrome (ACS) have low HDL-C levels. Currently, the association of very low levels of HDL-C with early mortality in patients with ACS is still a topic of considerable interest. However, the possible mechanisms are not clear. Since an acute coronary syndrome induces an inflammatory response, and several chronic systemic diseases and acute critical illnesses with clear pro-inflammatory components have been associated with significantly reduced HDL-C levels, and investigators have shown an inverse correlation between HDL-C levels and the levels of pro-inflammatory cytokines, we hypothesized that reduced HDL-C levels in acute coronary syndrome might be associated to inflammatory mediators. We therefore sought to evaluate the correlation between HDL-C levels and biomarkers of inflammation available in routine laboratory screenings (high-sensitivity C-reactive protein (hs-CRP), white blood cell (WBC) count, and serum albumin) in a retrospective cross-sectional study of patients with ST-elevation myocardial infarction (STEMI) or non-ST-elevation ACS (NSTE-ACS).

Medical Research: What are the main findings?

Dr. González-Pacheco: We found that approximately one-fifth of patients had very low HDL-C levels (<30 mg/dL). Baseline levels of hs-CRP were significantly higher in these patients than in those with low (30–39.9 mg/dL) and normal (≥40 mg/dL) HDL-C levels. In contrast, serum albumin values were lower in patients with very low HDL-C levels. WBC count did not differ significantly. Accordingly, hs-CRP levels ≥ 10 mg/L and serum albumin levels ≤ 3.5 mg/dL, were two strong independent predictors of very low HDL-C levels. We observed that patients with STEMI had higher expression of biomarkers of inflammation and lower levels of HDL-C, compared with NSTE-ACS patients, as well as a lack of significant difference in the extent of coronary disease among the categories of HDL-C levels. These findings suggest that the fall in HDL-C levels is in accordance with the severity of the inflammatory response and the extent of the myocardial damage. Our findings are consistent with previous studies, in which patients with very low HDL levels had a higher rate of in-hospital mortality compared with those of other HDL-C levels.

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No Evidence of Anti-Inflammatory Mediator Increase From Fish Oil Ingestion

Carsten C. Skarke MD Research Assistant Professor of Medicine McNeil Fellow in Translational Medicine Institute for Translational Medicine and Therapeutics Perelman School of Medicine University of PennsylvaniaMedicalResearch.com Interview with:
Carsten C. Skarke MD
Research Assistant Professor of Medicine
McNeil Fellow in Translational Medicine
Institute for Translational Medicine and Therapeutics
Perelman School of Medicine
University of Pennsylvania

Medical Research: What is the background for this study? What are the main findings?

Dr. Skarke: A growing body of publications suggests anti-inflammatory actions of fish oils. These health benefits are proposed to emerge from lipids called specialized pro-resolving mediators, (SPMs), which can be formed from omega-3 polyunsaturated fatty acids found in fish. A limitation to date, though, in this field is that there is little evidence of their formation in humans. And the cases where presence of these lipids is reported in humans, less rigorous analytical approaches, such as enzyme immunoassay (EIA), radioimmunoassay (RIA) or mass spectrometry without internal authentic standards, have been used. Thus, the specific aim for our study was to use state-of-the-art mass spectrometry to identify and quantify these specialized pro-resolving mediators.

Several aspects of our study design set us apart from what was done in previous studies.

  • First, we biased our ability to detect SPMs formed in healthy volunteers by giving fish oil in high doses which had been previously shown to influence blood pressure and platelet aggregation under placebo-controlled conditions.
  • Second, we also looked at lower doses of fish oil, those more commonly consumed by the general public, for the formation of SPMs during an acute inflammatory response and its resolution.
  • Third, we relied in our measurements of SPMs on authentic internal standards. These deuterated lipids, d4-resolvin E1 for example, facilitate distinct identification of the naturally formed lipid.
  • And fourth, we achieved very low limit of detection levels, below 10 pg/ml for resolvin E1, for example.

The surprising finding of our studies is that we failed to detect a consistent signal of SPM formation in urine or plasma of healthy volunteers who had taken fish oil. Even more surprising was that we found no alteration in the formation of SPMs during the resolution of inflammation. These results let us question the relevance of endogenous specialized pro-resolving mediators to the putative anti-inflammatory effects of fish oils in humans.

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Hispanics Have High Prevalence of Hyperlipidemia, but Low Awareness and Treatment

Carlos J. Rodriguez, MD, MPH Division of Public Health Sciences Department of Medicine Wake Forest School of Medicine Winston‐Salem, NC 27152MedicalResearch.com Interview with:
Carlos J. Rodriguez, MD, MPH
Division of Public Health Sciences
Department of Medicine Wake Forest School of Medicine
Winston‐Salem, NC 27152

MedicalResearch: What prompted you to study cholesterol in the Latino population? Please explain in detail.

Dr. Rodriguez: Early in my career I noted that there were race-ethnic differences in the cholesterol profile between hispanics, african americans and non-hispanic whites. Hispanics are the largest ethnic minority group in the us yet prior studies of cholesterol in hispanics were relatively small, lacked adequate representation of diverse hispanic background groups for comparisons, and were not necessarily representative of nor generalizable to the hispanic population. The hispanic/latino adults in the hispanic community health study / study of latinos helped filled this critical gap.

MedicalResearch: What do you think are the most significant findings from your study? What could have the greatest clinical implications and applications?

Dr. Rodriguez: Several findings are important: less than half of those with high cholesterol were aware of their condition; less than a third of those with high cholesterol were being treated; and  among those receiving treatment, only two-thirds had cholesterol concentrations that were adequately controlled.

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Pediatric Transition To Adult Lipid Control Guidelines Need Clarification

Holly Gooding, MD, MS Harvard T.H. Chan School of Public Health Instructor in Pediatrics at Harvard Medical School Division of Adolescent/Young Adult Medicine, Boston Children’s Hospital Division of General Internal Medicine, Brigham and Women’s Hospital Boston, MAMedicalResearch.com Interview with:
Holly Gooding, MD, MS
Harvard T.H. Chan School of Public Health
Instructor in Pediatrics at Harvard Medical School
Division of Adolescent/Young Adult Medicine, Boston Children’s Hospital Division of General Internal Medicine
Brigham and Women’s Hospital Boston, MA

Medical Research: What is the background for this study? What are the main findings?

Dr. Gooding: As an adolescent medicine physician, I primarily care for patients between the ages of 12 and 30, although I first trained in internal medicine.  One of the things I noticed when I started working with this age group is that pediatric and adult guidelines differ for many conditions.  Cholesterol treatment is one condition that comes up frequently, because the NHLBI and the AAP recommend screening youth ages 17 to 21 for cholesterol problems.

The study team and I set out to discover the proportion of American youth ages 17 to 21 who would meet criteria for pharmacologic treatment of abnormal cholesterol levels if clinicians applied the pediatric versus the adult guidelines.  We found that 2.6% of young people ages 17 to 21 would qualify for pharmacologic treatment of abnormal LDL cholesterol levels under the pediatric guidelines, but less than 1% would qualify under the adult guidelines.  This translates to almost 500,000 youth qualifying for treatment under the pediatric guidelines, but only about 78,000 under the adult guidelines.  Those who met pediatric criteria had lower LDL levels but higher proportions of high blood pressure, smoking, and obesity.

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Familial Hypercholesterolemia Linked To Lower Type2 Diabetes Risk

Joost Besseling PhD-student Academic Medical Center Dept. of Vascular Medicine AmsterdamMedicalResearch.com Interview with:
Joost Besseling PhD-student
Academic Medical Center
Dept. of Vascular Medicine
Amsterdam

Medical Research: What is the background for this study? What are the main findings?

Response: Statins are associated with an increased risk for type 2 diabetes mellitus (DM). The exact mechanism for this adverse event is largely unknown, although the upregulation of the low-density lipoprotein receptor (LDLR) has been suggested to play a role. In familial hypercholesterolemia (FH) the uptake of LDL-cholesterol via the LDLR is decreased due to a genetic defect. We found that the prevalence of type 2 DM is 50% lower in relative terms in patients with familial hypercholesterolemia. Moreover, there was a dose-response relationship: the more severe the genetic defect that causes familial hypercholesterolemia, the lower the prevalence of type 2 DM.
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Carotid Atherosclerosis Predicted by Cholesterol-Overloaded HDL Particles

MedicalResearch.com Interview with:
Dong Zhao MD.PhD Deputy Director & Professor andDong Zhao MD.PhD
Deputy Director & Professor and
Dr. Que Qi, MD.PhD Assistant Professor Beijing Institute of Heart,Lung & Blood Vessel Diseases Capital Medical University Beijing Anzhen HospitalDr. Que Qi, MD.PhD Assistant Professor
Beijing Institute of Heart,Lung & Blood Vessel Diseases
Capital Medical University Beijing Anzhen Hospital

Medical Research: What is the background for this study? What are the main findings?

Dr. Dong Zhao: Lower serum HDL-C level used to be considered as a key risk factor of atherosclerotic cardiovascular diseases. This knowledge was based on very consistent findings from researcher of basic science and observational studies of epidemiology. HDL-C has been also introduced as “good cholesterol” to the public. However, this well accepted knowledge was challenged when two large RCTs demonstrated that increased serum HDL-C by CETP inhibitor (ILLUMINATE and dal-OUTCOMES) failed to show benefits on reducing the risk of atherosclerotic cardiovascular disease. Therefore, many researchers questioned whether serum HDL-C can fully represent the capacity of cholesterol reverse transport of HDL particle, an underpinning of the anti-atherogenic function of HDL. And HDL particle number was considered to be better than HDL-C as a proper parameter to assess the function of HDL. In fact, RCTs that increased serum HDL-C substantially by CETP inhibitor had little effect on HDL particle number, thus resulting in increased cholesterol-overloaded HDL particle. Previous experimental studies observed that cholesterol-overloaded HDL particle exerted a negative impact on cholesterol reverse transport. However, it remains unclear whether cholesterol-overloaded HDL is involved in the development of atherosclerosis in humans. In our study, we measured HDL particle number using nuclear magnetic resonance spectroscopy, and calculated the ratio of HDL-C to HDL particles number to estimate the cholesterol content per HDL particle (HDL-C/P ratio). We found that cholesterol-overloaded HDL particles, indicated by high HDL-C/P ratio, are independently associated with the progression of carotid atherosclerosis in asymptomatic individuals from a community-based cohort study of the Chinese Multi-provincial Cohort Study-Beijing Project.

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Personalized Genetic Profile Determines Benefit of Dalcetrapib for Heart Disease

Jean-Claude Tardif MD Professor of Medicine Director of the Research Centre Montreal Heart Institute Montreal, Quebec CanadaMedicalResearch.com Interview with:
Jean-Claude Tardif MD
Professor of Medicine
Director of the Research Centre
Montreal Heart Institute Montreal, Quebec Canada

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Tardif: Epidemiological and mechanistic studies have suggested that high-density lipoproteins (HDL) could have beneficial cardiovascular properties. However, several medications targeting HDL have failed in recent clinical trials, including the CETP inhibitor dalcetrapib in the dal-Outcomes trial. We hypothesized that dalcetrapib would be beneficial in the subset of patients with the appropriate genetic profile. We conducted the pharmacogenomic analysis of approximately 6000 patients from the dal-Outcomes study which showed that patients with the AA genotype at a specific genetic location (rs1967309) of the adenylate cyclase (ADCY9) gene benefited from a 39% reduction in cardiovascular events including cardiovascular death, myocardial infarction, stroke, unstable angina and the need for coronary revascularization when treated with dalcetrapib compared to placebo. In contrast, patients with the GG genotype had a 27% increase in cardiovascular events. We then obtained confirmatory evidence from the dal-Plaque-2 imaging study which revealed that patients with the protective genotype (AA) had a reduction in their carotid artery wall thickness and that those with the genotype associated with clinical harm (GG) had an increase in their wall thickness.

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Lipid Metabolites in Blood Predictive of Future Coronary Artery Disease

MedicalResearch.com Interview with:
Prof. Erik Ingelsson, MD, PhD, FAHA

Professor of Molecular Epidemiology and
Andrea Ganna PhD student
Uppsala University

Medical Research: What is the background for this study? What are the main findings?

Response: Coronary heart disease (CHD) comprises a major cause of morbidity and mortality throughout the world. Measurement of metabolites, small molecules, in the blood could allow earlier diagnosis and inform about mechanisms leading to CHD. We examined the metabolic profiles (including thousands of metabolites) of blood samples from more than 3,600 individuals from Sweden that had been followed-up for up to 10 years, and found two lipid-related metabolites, lysophosphatidylcholine and sphingomyelin that reduced the risk of developing coronary heart disease and another lipid metabolite, monoglycerides, that was instead associated with increased risk.

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Apolipoprotein E Research May Open New Door to Alzheimer Research

MedicalResearch.comInterview with:
Mary Malloy, M.D.
Co-director of the Adult Lipid Clinic and the director of the Pediatric Lipid Clinic
UCSF Medical Center

Medical Research: What are the main findings of the study?

Dr. Malloy: We studied an individual whom we found to be homozygous for a rare loss of function mutation in apolipoprotein E.

Because apolipoprotein E is necessary for clearance of lipoproteins from plasma, he has very high levels of cholesterol and triglycerides in blood, and unusual and very severe xanthomas. He had no evidence of neurocognitive or retinal defects.
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Evolocumab For Resistant Familial Hypercholesterolemia

MedicalResearch.com Interview with:
Dr. Raul Santos
Unidade Clínica de Lipides InCor-HCFMUSP
Sao Paulo, Brazil.

Medical Research: What are the main findings of the study?

Dr. Santos: Evolocumab 420 mg injected subcutaneously every 4 weeks reduced LDL-C by 31% on average, in relation to placebo, in Homozygous familial hypercholesterolemia patients that were using maximally tolerated lipid lowering therapy but not on lipid apheresis regimen. Patients were separated according to the type of LDL receptor mutation, those with at least one allele codifyng a defective mutation on the LDL receptor (residual receptor activity 2-25%) had on average a 41% reduction on LDL-cholesterol. The 2 patients  homozygotes with alleles that codify a null mutation )receptor activity < 2%), did not respond to treatment. This was expected since PCSK9 inhibitors need a functional LDL receptor do work. Basically they increase the expression of the receptor that facilitates the clearance from plasma of circulating LDL particles. In those patients with defective LDL receptor  mutations there was 24% reduction of lipoprotein(a) concentrations, an extra risk factor for cardiovascular disease in familial hypercholesterolemia patients.

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Statins May Have Additional Lipid Profile Benefit in Pre-Diabetes

Prof. Moses Elisaf Professor of Internal Medicine University of Ioannina, GreeceMedicalResearch.com Interview with:
Prof. Moses Elisaf
Professor of Internal Medicine
University of Ioannina, Greece


Medical Research: What are the main findings of the study?

Dr. Elisaf: We evaluated the effects of rosuvastatin in two groups of hyperlipidemic patients: one group had impaired fasting glucose (IFG) while the second group had normal fasting glucose. After study end, both groups had similar changes in their lipidemic profile.

However, patients with IFG had a significant greater decrease in the cholesterol concentration of the more atherogenic small dense low-density lipoprotein (sdLDL) particles (-65.7%) compared with controls (-38.5%). Moreover, a greater increase in the mean LDL particle size was observed in the impaired fasting glucose group (+1.5% vs +0.4%).

In addition, redistribution from the more atherogenic sdLDL to large buoyant
LDL (lbLDL) subfractions was observed in the IFG group.
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